This application seeks funding for my scientific investigations into the pathogenesis of and possible clinically translatable interventions for autoimmune type 1 diabetes (T1D). These studies will serve as a basis for my future research program, positioning me for an academic faculty position. Having an initial background as a clinical DVM provides me a broad base on which I am building my scientific research career using mouse models of human autoimmune diseases. I successfully completed my Ph.D. in the winter of 2011 and am continuing to work towards my goal of becoming an independent researcher. Having studied the B-lymphocyte mediated, T-cell dependent disease systemic lupus erythematosus (SLE) for my Ph.D. work, I wished to broaden my autoimmunity knowledge base by transitioning to investigating the T-cell mediated, B lymphocyte dependent disease, T1D. Having made this transition approximately a year ago, my immediate goals are to continue building upon my knowledge of autoimmune disease pathogenesis as well as gain new tools for this area of research. Funding of this proposal would allow me to expand my knowledge of autoimmunity as well as familiarize myself with additional research techniques. In addition, several publications should be possible from this work as well as the progression of ideas for an R01 application in the coming years. All of these efforts enabled with this proposal will greatly increase my chances of success in my next position as an independent academic faculty member. The Jackson Laboratory is an ideal location to perform the studies in this proposal using mouse models of human disease. The institute has state of the art scientific facilities as well as a wealth of exceptionally knowledgeable faculty and staff to assist me with my work. In addition, The Jackson Laboratory provides venues in which important outside researchers from around the world come to speak including a weekly lecture series as well as annual conferences. An NIH-approved program is also in place for continued training in research ethics. My mentor, Dr. David Serreze, is a world-renowned senior researcher in the field of autoimmune diabetes and has graduated many successful trainees to independent positions in both academia and industry. His laboratory and resources are well established and well funded and he is committed to supporting my endeavors. My co-mentor Dr. Kevin Mills is also a leader in his field, having recently published important works on immunological areas key to elements of this proposal and has pledged to assist me in any way possible in pursuing the aims in this application. The Jackson Laboratory and its personnel will ensure I receive all the support necessary to successfully complete the scientific goals of this proposal as well as aid in my transition to an independent researcher. T1D in both humans and the NOD mouse model ultimately results from T cell mediated autoimmune destruction of insulin producing pancreatic ? cells. However, in NOD mice, and also likely in humans, B- lymphocytes play a key role in driving diabetogenic T-cell responses. The scientific goals of this application seek to optimize B-lymphocyte targeted therapeutic interventions for T1D. Several different B-lymphocyte directed therapies have been successful at attenuating progression to T1D when initiated at early stages of disease development in NOD mice including the rituxamib-like anti-CD20 antibody and BAFF blockade. However, humans at high future risk for T1D can currently only be identified after manifesting signs of ongoing high levels of ? cell destruction such as the presence of circulating autoantibodies. Thus, clinically translatable T1D interventions must be effective when initiated at late stages of disease development. In recent onset human T1D patients, transient therapy with the CD20 specific rituximab antibody provided only marginally effective at clinical disease attenuation. A possible explanation for this weak effect may stem from previous findings by our group that some B-lymphocyte populations in NOD mice, including those infiltrating pancreatic islets, are resistant to deletion by rituximab-like anti-CD20 therapy. One goal in this proposal is to understand to what extent B-lymphocyte subpopulations that are resistant to anti-CD20 mediated deletion contribute to various stages of T1D progression, and to investigate alternative therapeutic approaches to repress these cells. Another goal is to determine the importance of B-lymphocyte affinity maturation for antigen in T1D pathogenesis and includes the testing of a novel therapeutic approach borrowed from the lymphoma field that targets this process. When initiated at late stages of T1D development, the best therapeutic outcomes may be obtained with combination therapies, and the experiments in this proposal will address this possibility. The overall importance of this proposal lies in the identification of B-lymphocyte directed T1D therapies most effective at late stages of disease development as this information will be of highest clinically translatable relevance.